PROJECT SUMMARY Although high-sugar diets and metabolic disease are known to have negative effects on the reproductive system and fertility, the cellular and molecular mechanisms that link diet to gamete survival and quality are unknown. Our long-term goal is to elucidate the molecular mechanisms that regulate fertility in response to a high-glucose diet using C. elegans, an excellent experimental system for elucidating the cellular underpinnings of glucose toxicity and fertility. As in humans, a high-glucose diet reduces fertility in C. elegans hermaphrodites. The objectives of this proposal are to identify the relevant cellular phenotypes and genetic pathways associated with the loss of fertility on a high-glucose diet, using both C. elegans males and hermaphrodites as complementary experimental systems. The central hypothesis is that a high-glucose diet limits fertility by reducing both gamete survival and gamete quality via sex-specific mechanisms, an idea supported by preliminary data in the applicant?s laboratory. The rationale for the proposed research is that successful completion will contribute to our fundamental understanding of how different types of gametes respond differently to a high-glucose diet and how a high-glucose diet reduces cell survival and quality, key contributors to infertility, which affects 15% of Americans of reproductive age. The hypothesis will be tested by pursuing two specific aims: 1) define the cellular phenotypes and pathways that regulate oocyte survival and quality on a high-glucose diet and 2) define the cellular phenotypes and pathways that regulate sperm survival and quality on a high-glucose diet. Preliminary data suggest that apoptosis is required for a high-glucose diet to reduce hermaphrodite fertility, and in the first aim a physiological and genetic analysis will be used to understand which conserved apoptosis regulatory pathways modulate oocyte survival, and whether oocyte quality also declines on a high-glucose diet. Preliminary data using the under-studied C. elegans male demonstrate that a high-glucose diet also reduces male fertility, but suggest that decreased sperm quality, rather than increased sperm apoptosis, is responsible. In the second aim, the origin of the reduced sperm quality on a high-glucose diet will be determined, and a genetic analysis will test the role of non-apoptotic pathways in sperm survival. The approach is innovative because it uses male C. elegans as a complementary model to uncover novel cellular and molecular responses to a high-glucose diet, in keeping with the spirit of the call to consider sex as a biological variable in pre-clinical studies. Using both sexes will allow discovery of additional cellular responses to a high-glucose diet and definition of which of these are likely to be ?universal? and which may be sex- or cell-type specific. The proposed research will be significant because it will advance our understanding of the variety of ways in which a high-glucose diet regulates gamete survival and quality defects, which underlie infertility. Given rates of dietary sugar consumption, obesity, and type 2 diabetes, there is a critical need to understand how gametes respond to glucose toxicity in order to identify potential strategies to protect and maintain gamete quality, gamete survival, and fertility.